Coronavirus 19 (COVID-19) is a viral respiratory disease that was identified in December 2019 after the first cases in China, spreading rapidly until reaching pandemic status, causing the collapse of numerous health systems and strong economic and social impact. By the end of April 2020, 3.08 million cases, and more than 214 thousand deaths were already recorded. The treatment so far has not been established and there are several clinical trials testing known drugs that have antiviral activity in vitro, due to the urgency that the global situation imposes. Medicines with specific actions can take years to be discovered, while a vaccine also takes a long time. Recently, it has been shown that the worsening of Coronavirus infection may be related to the formation of micro clots in blood vessels and anticoagulants have been used as adjuvants in the treatment. This study is justified by conducting a pilot study that showed an in vitro antiviral action (anti-COVID-19) of high molecular weight heparin. Methods: A phase I / II clinical trial will be conducted. 40 participants will be included in two arms. Participants allocated to Group 1 (control) will receive inhalation with 0.9% saline applied 4/4 hours, for 7 days. Participants allocated to Group 2 (intervention) will receive high molecular weight inhaled heparin (250ug / mL 0.9% SF), at a 4/4 hour dose, for 7 days. The outcomes of interest will be safety (absence of moderate or serious adverse events) and effectiveness (measured in a score of 7 points, with 1 absence of limitations and 7, death). Expected results: The development of a new therapeutic option for COVID-19 is expected, with the possibility of use in other serious coronavirus diseases, to be subsequently tested in phase III studies.
In view of the enormous health, financial and social crisis resulting of the pandemic caused
by SARS-Cov-2, it is justified to urgently conduct tests with possible antiviral drugs. The
high molecular weight heparin (HMWH) (heparin enriched by ultrafiltration process) proposed
by this study, has a potential inhibition activity over viral replication, demonstrated by
preliminary in vitro tests, carried out in a model established in partnership with the
Laboratory of Clinical and Molecular Virology (LVCM) of the Institute of Biomedical Sciences
of the University of São Paulo (ICB-USP).
Along with the findings in the literature, such as the study carried out by Phelps, M.K. et
al (2020), among others, the use of inhaled heparin presents adequate levels of safety to be
used in a clinical trial. Taking into account that the dose of high molecular weight heparin
(enriched by this study team) with antiviral activity in vitro is much lower than the doses
currently presented in published clinical trials using inhaled UFH, we have the safety
premise to carry out this study. The intentions of this study differ from what has been
presented in the world literature so far, as it does not aim to induce anticoagulation, nor
to effectively inhibit the formation of pulmonary fibrin, but rather, to act as an inhibitor
of viral replication.
Also, as characteristics of the product to be tested, this heparin (HMWH) is presented in a
buffered solution free of low-sulfated low-weight molecules, which is obtained in a sterile
environment through ultrafiltration of the unfractionated solution of porcine origin
available in Brazil (Hemofol - Cristália) using Centriprep-10kDa® centrifuge filter
(Millipore ™) used as recommended by the manufacturer.
The high molecular weight heparin (HMWH) - enriched heparin - had two process patents filed,
one under the description "HIGH MOLECULAR WEIGHT DEFINITION HEPARINE DEVELOPMENT PROCESS", BR
102014027804-4 A2 - granted by the Instituto Nacional de Propriedade Industrial (INPI) and
another with the description "COMPOSITION OF HIGH MOLECULAR WEIGHT NON-FRACTIONAL HEPARINE
FOR ANTIVIRAL ACTION ", BR 102020 011964-8 - deposited at INPI.
Drug: Heparin sodium
Nebulized inhalation of 5 mL of a solution containing high molecular weight heparin - enriched heparin - 2.5mg/mL and 0.9% saline solution, every 4 hours for 7 days, except during the nighttime (5 doses/day)
Other Name: Hepamax S BLAU
Drug: Placebo
Nebulized inhalation of 5 mL of 0.9% saline solution, every 4 hours for 7 days, except during the nighttime (5 doses/day)
Other Name: Array
Inclusion Criteria:
- Signature and agreement to the Free Consent Form;
- Both sexes, of any ethnic origin, aged between 18 and 90 years;
- COVID-19 infected patients diagnosed by RT-PCR (reverse-transcriptase polymerase chain
reaction) or with a strong suspicion of COVID-19 by clinical evaluation through
compatible clinical and radiological findings;
- Time of disease evolution less than 10 days;
- Radiological diagnosis of grade 2A pneumonia, with gas exchange ratio > 200 on blood
gas analysis (paO2 / pFiO2), characterizing mild hypoxemia;
- Indication of hospital treatment regime, provided that the period of hospitalization
before inclusion is not more than 24 hours;
- Need for supplemental oxygen therapy (O2) less than 5L / min.
Exclusion Criteria:
- No agreement to the terms of this study;
- Moderate or severe respiratory failure requiring admission to the ICU and the need for
invasive mechanical ventilation or non-invasive ventilation (NIV) with positive
pressure;
- Pregnancy or puerperium;
- Patients with hematological diseases, coagulation disorders, use of anticoagulants,
previous heparin-induced allergy or thrombocytopenia, thrombocytopenia with a count of
fewer than 50,000 platelets / mm3;
- COVID-19 not confirmed by RT-PCR within 72 hours of inclusion in the study.
Hospital das Clinicas de Boucatu
Botucatu, Sao Paulo, Brazil
School of Medicine at Botucatu- Paulista State University- UNESP, São Paulo, Brazil
Botucatu, SP, Brazil
Matheus Bertanha, PhD
+55(14)3880-1444
matheusbertanha@gmail.com
Carlos Magno CB Fortaleza, PhD
+55(14)3880-1284
carlos.fortaleza@unesp.br
Matheus Bertanha, PhD, Principal Investigator
São Paulo State University (Unesp)